tbuckley/cabot-search huggingface dataset:
IGNITE: A phase II signal-seeking trial of adavosertib targeting recurrent high-grade, serous ovarian cancer with cyclin E1 overexpression with and without gene amplification.
Authors: George Au-Yeung, Mathias Bressel, Owen Prall, Daniela Surace, John Andrews, Sally Mongta, Yeh Chen Lee, Bo Gao, Tarek Meniawy, Sally E. Baron-Hay, Allison Jane Black, Ganessan Kichenadasse, Sumitra Ananda, Peter Fox, David Bowtell, Linda R. Mileshkin
Journal: Journal of Clinical Oncology (2022)

5515 Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC with cyclin E1 over-expression, with and without gene amplification. Methods: IGNITE is a multicentre, phase 2 trial with 2 cohorts of women with recurrent platinum resistant HGSC. Tumors were assessed for cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients were assigned to Cohort 1 if tumors were cyclin E1 over-expressed (H-score&gt;50) and amplified (≥8 copies), and Cohort 2 if tumors were overexpressed and nonamplified. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was investigator assessed clinical benefit (CB) defined as absence of progression for ≥ 18 weeks. Here we present the 18-week response data for the first 32 patients treated from Cohort 2, with a data cut-off of August 2021. Results: Between Jan-2020 and May-2021, 32 patients were accrued to Cohort 2. Median age was 62 years (range 42-77) and 84% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 120 and 28 patients (88%) had measurable disease by RECIST. Median number of cycles commenced was 8 (range 1-19). Overall response rate (ORR) was 53% and CB rate was 61% for all evaluable patients. Seventeen patients (53%) required a dose reduction, most commonly for neutropenia or fatigue. Seventeen patients experienced ≥Grade 3 treatment related adverse event, and 4 patients (15%) discontinued due to toxicity. Conclusions: The efficacy results in a biomarker-selected cohort of patients are promising with a higher response rate than reported in previous studies of adavosertib in unselected women with recurrent HGSC. Duration of response and progression free survival data will be presented as data matures. Clinical trial information: ACTRN12619001185156P. [Table: see text]
Effectiveness of oral aciclovir in preventing maternal chickenpox: A comparison with VZIG
Authors: Bersabeh Sile, Kevin E Brown, Charlotte Gower, Johanna Bosowski, Amanda Dennis, Michelle Falconer, Julia Stowe, Nick Andrews, Gayatri Amirthalingam
Journal: Journal of Infection (2022)

Although often presenting as a self-limiting childhood disease, chickenpox can have serious consequences if acquired in pregnancy. Until April 2022, the UK recommendations were that varicella immunoglobulin (VZIG) should be administered intramuscularly to susceptible pregnant women exposed to chickenpox prior to 20 weeks gestation. Oral aciclovir or VZIG was recommended if exposure occurred at 20+ weeks gestation. Our objective was to compare the effectiveness of oral aciclovir to VZIG in preventing maternal and neonatal chickenpox.We identified and followed up 186 pregnant women who were exposed to chickenpox and compared their outcomes.171/186 (91.9%) of these women received either VZIG or oral aciclovir. Of the 145 women who received VZIG, 53/145 (36.6%) went on to develop chickenpox compared to 8 of the 26 (30.8%) women who received oral aciclovir (p = 0.32). No statistical difference was found between the oral aciclovir and VZIG groups even after controlling for maternal age, gestational stage, type of exposure and IgG titre (adjusted OR:0.83; 95%CI:0.26-2.65; p = 0.75).These findings support the use of oral aciclovir as first-line prophylaxis in pregnant women exposed to varicella as they suggest its effectiveness at preventing maternal chickenpox is either better or equal to VZIG.
Optimization of treatment options for EGFR-mutant, stage III, unresectable NSCLC: A systematic review and meta-analysis.
Authors: Lian Liu, Xin Dai, Song Li, Lei Sheng, Kai Huang, Jiahui Chu, Jian Wang, Jisheng LI, Yanguo Liu
Journal: Journal of Clinical Oncology (2022)

8548 Background: The PACIFIC study established a new treatment standard for Stage III unresectable NSCLC, but CRT followed by durvalumab failed to bring survival benefit to patients with EGFR mutations. EGFR-TKIs have been successful in the setting of first-line treatment of advanced NSCLC and postoperative adjuvant treatment of NSCLC. We explored whether locally advanced inoperable patients with EGFR mutations can benefit from EGFR-TKIs and the possibly best treatment regimen through meta-analysis. Methods: Studies involving unresectable stage III NSCLC with EGFR mutations published in PubMed, Embase, Cochrane, ClinicalTrials.gov, and abstracts of important international conferences (ASCO, ESMO, WCLC) from January 1, 2000 to September 30, 2021 were screened. An integrative analysis was performed using STATA (version 16.0), and a network meta-analysis based on a Bayesian framework was performed using R (version 3.6.1) for the studies with a control group. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 3291 patients were identified in 17 studies, including 5 treatment measures including concurrent chemoradiotherapy (CRT), CRT followed by durvalumab (CRT+Durva), TKI monotherapy, radiotherapy combined with TKI (RT+TKI), and CRT combined with TKI (CRT+TKI). PFS with TKI-free treatments (CRT, CRT+Durva) was significantly shorter than TKI-containing ones (TKI, RT+TKI, CRT+TKI) (HR 2.17, 95%CI 1.47-3.19), but its advantage only translated into borderline OS benefit (1.27, 0.99-1.63). In detail, the PFS with TKI-containing measures, including TKI monotherapy (0.66, 0.50-0.87), RT+TKI (0.37, 0.28-0.50), or CRT+TKI (0.14, 0.03-0.75) were all significantly longer than CRT. Furthermore, the PFS with both RT+TKI (0.40, 0.21-0.76) and CRT+TKI (0.15, 0.03-0.74) were significantly longer than CRT+Durva, while no statistical difference existed in PFS between RT+TKI and CRT+TKI. However, TKI alone had significantly shorter PFS than RT+TKI (1.78, 1.17-2.67). There was no statistical difference in OS among all the treatments, with RT+TKI ranking first in the Bayesian ranking. The integrated analysis found that RT+TKI had the longest OS (65.7 months, 55.5-76.0 months) and PFS (21.8 months, 18.0-25.7 months) and the highest response rate (77.7%, 68.8%-86.6%). Severe neutropenia was the most common with CRT+TKI, while RT+TKI brought the highest incidences of radiation pneumonitis and esophagitis. Conclusions: For EGFR mutant Stage III unresectable NSCLC, RT and TKI are both essential. RT+TKI and CRT+TKI have significantly longer PFS than CRT±immunotherapy, and RT+TKI has OS benefit trends. Due to the lack of sufficient studies on CRT+TKI, it is urgent to conduct large randomized clinical trials to explore the optimal treatment for these patients.
Association of Tumor Characteristics With Insurance Type Among Patients Undergoing Mohs Micrographic Surgery for Nonmelanoma Skin Cancer
Authors: Emily L. Clarke, Tyler J. Willenbrink, Megan Shelton, Aneeqah Naeem, James Custer, Ashley D. Lundgren, William D. Boothe, Paul J. Rathouz, Adewole S. Adamson, Matthew C. Fox, Anokhi Jambusaria-Pahlajani
Journal: JAMA Dermatology (2022)

<h3>Importance</h3> Little is known about the association between insurance type and tumor or treatment characteristics among patients undergoing Mohs micrographic surgery (MMS) for nonmelanoma skin cancer (NMSC). <h3>Objective</h3> To investigate whether there are differences in tumor and treatment characteristics among patients undergoing MMS for NMSC by insurance type. <h3>Design, Setting, and Participants</h3> This retrospective cohort study included patients with NMSC who presented for surgery at an academic MMS practice between May 2017 and May 2019. <h3>Main Outcomes and Measures</h3> Preoperative and postoperative tumor diameters, number of MMS stages, type of closure, and number of high-risk tumors were compared based on insurance type among uninsured and underinsured patients and those with private insurance, Medicare, and Veterans Affairs (VA) insurance. <h3>Results</h3> A total of 1397 patients with NMSC (978 [70%] male; mean [SD] age, 68.5 [12.4] years) underwent 1916 MMS procedures. Of these patients, 868 (45%) had Medicare, 570 (30%) had private insurance, 299 (16%) had VA insurance, and 179 (9%) were treated at a safety net clinic or were uninsured. Compared with patients with private insurance, uninsured and underinsured patients had significantly larger preoperative tumor bed diameters (difference, 28%; 95% CI, 14%-43%;<i>P</i> &lt; .001) and postoperative defect sizes (difference, 28%, 95% CI, 16%-41%;<i>P</i> &lt; .001). Patients with Medicare and VA insurance did not have significantly different preoperative tumor bed diameters compared with patients with private insurance. Patients with VA insurance had larger postoperative defect sizes than patients with private insurance (difference, 12%; 95% CI, 2%-23%;<i>P</i> = .02). The number of MMS stages and type of closure did not significantly differ based on insurance type. <h3>Conclusions and Relevance</h3> In this cohort study of patients undergoing MMS for NMSC, larger preoperative tumor and postoperative defect sizes were associated with being uninsured or underinsured compared with privately insured. Future studies are required to determine why these differences exist to deliver optimal care to all patients.
IMMU-18. Targeting Antigen Presenting Cells to improve virotherapy efficacy in Diffuse Midline Gliomas
Authors: Sara Labiano, Javier Marco-Sanz, Virginia Laspidea, Marc Garcia-Moure, Montserrat Puigdelloses, Iker Ausejo, Reyes Hernández-Osuna, Oren Becher, Ana Patiño-Garcia, Candelaria Gomez-Manzano, Juan Fueyo, Marta M Alonso
Journal: Neuro-Oncology (2022)

Abstract With a 2-year survival less than 20%, Diffuse Intrinsic Pontine Glioma (DIPG) is the principal cause of pediatric death. Despite recent advances in the current treatments, the outcome for children with DIPGs remains dismal. Since the approval of T-VEC for melanoma by the FDA, oncolytic adenoviruses have emerged as a promising therapeutic strategy for brain tumors. Thus, our group launched the first world clinical trial phase I with the oncolytic adenovirus Delta-24-RGD (DNX-2401 in the clinic) for newly diagnosed DIPG (NCT03178032), which has shown safety and feasibility. Despite DNX-2401 increases the recruitment of T cells into the tumor, they usually become inactive due to the non-responsive tumor microenvironment evidencing the urgent need to improve this strategy focusing on the generation of effective long-term immune responses. Therefore, we decided to combine the Delta-24-RGD with the targeting of the costimulatory molecule CD40 in immunocompetent mice bearing orthotopic DIPG. The activation of the CD40 receptor, which is expressed by antigen presenting cells (APC) such as microglia, macrophages, and dendritic cells, is known to increase antigen presentation and enable T-cell priming and activation. Here, we observed that in addition to Delta-24-RGD anti-tumor effects, the stimulation of CD40 (using an agonistic antibody) on the tumor APCs results in a remodeling of the tumor immune compartment towards a proinflammatory scenario and a more efficient T-cell infiltration. Of importance, the combination therapy extends survival of treated mice as compared to single treatments or non-treated mice. In addition, we observe a complete regression of tumors in more than 40% of treated mice and the development of long-term anti-tumor immunity. We believe that these results provide a translational breakthrough in the treatment of these lethal tumors and open the door for a future innovative clinical trial.
A novel immune cell signature predicts pathological complete response to neoadjuvant chemotherapy in triple negative breast cancer patients in the Q-CROC3 trial.
Authors: Mark Basik, Yixiao Zeng, Adriana Aguilar, Katy Milne, Josiane Lafleur, Livia Florianova, Olga Aleynikova, Cristiano Ferrario, Jean-Francois Boileau, Elizabeth A. Marcus, Yohann Pilon, Dorsai Ranjbari, Federico Discepola, Celia Greenwood
Journal: Journal of Clinical Oncology (2022)

e12614 Background: Tumor infiltrating lymphocytes (TILs) have been associated with good prognosis and response to neoadjuvant chemotherapy. Several reports have shown that the heterogeneity of tumor infiltrating immune cells affects the response to chemotherapy, with for example low levels of FOXP3 expressing T cells associated with good prognosis and pathological complete response (pCR) to chemotherapy. Methods: We examined different immune cell markers on 52 pre-chemotherapy biopsy specimens obtained from triple negative breast cancer patients undergoing neo-adjuvant chemotherapy from the Q-CROC-03 trial. Slides were stained for CD8, CD3,PD-1, PDL-1, FOXP-3 and Granzyme B using multi-colour immunohistochemistry and automated cell counting of stroma and epithelial counts was conducted using the Vectra/inForm image analysis platform. We had total of 39 variables for analysis and we performed Penalized logistic regression for variable selection. Results: Nine variables were found statistically significant to predict response to chemotherapy, PD1+ stroma counts being the one with the highest probability of association with response. A tree algorithm was then used on all 9 variables to identify the best variable and threshold combination to identify patients who respond to chemotherapy. We separated our cohort in test (25% of samples n = 13) and training (75% of samples n = 39) sets for this analysis. Restricting the tree depth to 2 variables for clinical interpretability identified the combination of average counts of stromal PD1+ and average density of stromal FOXP3+ as predictors of chemo response (accuracy 0.82). Both stromal average PD1+ counts and average stromal FOXP3+ density positively correlated with the levels of TILS. Conclusions: Combining FOXP3 and PD1 protein expression in the stroma of pre-treatment biopsies of triple negative breast cancers receiving neoadjuvant chemotherapy is highly predictive of pCR.
LGG-52. Volumetry-based response characterization of recurrent pediatric low-grade gliomas in PNOC clinical Neuro-oncology trials
Authors: Marc von Reppert, MingDe Lin, Khaled Bousabarah, Ariana Familiar, Ryan Velasco, Angela Waanders, Arastoo Vossough, Amanda Haddock, Theodore Nicolaides, Kristin Swanson, Anahita Kazerooni, Cassie Kline, Ali Nabavizadeh, Daphne Haas-Kogan, Michael Prados, Joshua Rubin, Sabine Mueller, Mariam Aboian
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Endpoints in clinical trials using novel treatments are evaluated by RANO criteria, which provide an estimate of tumor size from two-dimensional measurements along the most prominent axial slice. However, pediatric low-grade gliomas (pLGG) commonly have variegated shapes with solid and cystic components, potentially resulting in misevaluation of true tumor volume and thus, ultimately, trial outcome. OBJECTIVES: We aim to characterize treatment response through volumetric assessment of progressive/recurrent pLGGs treated with single-agent everolimus on PNOC001 clinical trial. We seek to identify clinically relevant criteria that provide added value to response assessment beyond 2D measurements. METHODS: In a cohort of 44 patients we performed 3D-segmentation of solid, cystic and whole tumor within our PACS-framework and compared results to previously carried-out central imaging review by RANO criteria which had yielded 15 PD, 27 SD, 2 PR and 0 CR. RESULTS: 8 tumors were solid only and 36 had a mixed solid-cystic appearance. When evaluating the entire tumor (i.e. solid and cystic components combined) and using the same RANO cutoff criteria, one case changed from PR to SD, one changed from SD to PR, 3 changed from SD to PD, and 7 changed from PD to SD, resulting in an overall discordance of 27% of cases. CONCLUSION: We propose that incorporation of volumetrics into response assessment provides additional and potentially more accurate information beyond RANO-based measurements. It is crucial to note that the above-reported changes represent numerical discrepancies as opposed to true-to-reality changes in clinical outcome. Determining representative thresholds for the deployment of volumetric measures in clinical trials will be critical. Future work will include data from the PNOC002 clinical trial and evaluate inter-reader agreement and reader discordance. With the availability of PACS-based 3D-tools in neuroradiology practice, well-defined volumetric criteria could be incorporated prospectively into treatment response analysis in clinical trials.
LGG-59. Identifying hidden drivers of low-grade glioma tumor growth
Authors: Sean Misek, Aaron Fultineer, Alexandra Condurat, Kevin Zhou, David Root, Nicole Persky, Jesse Boehm, Pratiti Bandopadhayay, Rameen Beroukhim
Journal: Neuro-Oncology (2022)

Abstract Genomic drivers of pediatric low-grade gliomas (pLGGs) converge on alterations that activate the MAPK pathway. However, expression of individual driver oncogenes fails to induce tumor formation with high penetrance and, paradoxically, expression of these oncogenes suppresses growth in vitro. This, combined with the non-monotonic tumor growth rate in patients, suggests that there are “hidden drivers” beyond a single driver oncogene that are necessary to support tumor growth. The goal of this project is to leverage high-throughput functional genomics strategies to identify these hidden drivers of pLGG. Our preliminary data indicates that genes which modulate differentiation are required for the survival of LGG cells, suggesting that these genes may be hidden drivers of LGG tumor growth. Additionally, we hypothesize that secreted factors in the tumor microenvironment regulate pLGG tumor growth, potentially by modulating differentiation. In total, genes which cooperate with pLGG driver oncogenes to promote tumor growth may represent a new class of therapeutic targets and may explain the complex patterns of tumor growth that are observed in patients.
Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067.
Authors: F. Stephen Hodi, Vanna Chiarion -Sileni, Karl D. Lewis, Jean-Jacques Grob, Piotr Rutkowski, Christopher D. Lao, Charles Lance Cowey, Dirk Schadendorf, John Wagstaff, Reinhard Dummer, Paola Queirolo, Michael Smylie, Marcus O. Butler, Andrew Graham Hill, Ivan Marquez-Rodas, John B. A. G. Haanen, Piyush Durani, Peter Wang, Jedd D. Wolchok, James Larkin
Journal: Journal of Clinical Oncology (2022)

9522 Background: Durable clinical benefit has been achieved with nivolumab (NIVO) + ipilimumab (IPI), including an overall survival (OS) of 49% and a melanoma-specific survival (MSS) of 56%, with median MSS not reached (NR) at 6.5-y minimum follow-up. Here we report sustained efficacy outcomes at 7.5 y. Methods: Patients (pts) with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1:1 and stratified by PD-L1 status, BRAF mutation status, and metastasis stage to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) and OS with NIVO + IPI or NIVO alone versus IPI. Results: With a minimum follow-up of 7.5 y, median OS remained stable at 72.1 mo (NIVO + IPI), 36.9 mo (NIVO), and 19.9 mo (IPI); median MSS was NR, 49.4 mo, and 21.9 mo, respectively (Table). While the objective response rate remained stable at 58% (NIVO + IPI), 45% (NIVO), and 19% (IPI), median duration of response had now been reached for NIVO at 90.8 mo and remains NR and 19.2 mo for NIVO + IPI and IPI, respectively. Subsequent systemic therapy was received by 36%, 49%, and 66% of NIVO + IPI-, NIVO-, and IPI-treated patients, respectively, and median time to that therapy was NR (95% CI, 45.9–NR), 24.7 mo (16.0–38.7), and 8.0 mo (6.5–8.7). Of patients alive at 7.5 y, 106/138 (77%, NIVO + IPI), 80/115 (70%, NIVO), and 27/60 (45%, IPI) were off treatment and had never received subsequent systemic therapy. No change to the safety summary was observed with additional follow-up; updated health-related quality of life data will be reported. Of the 10 new deaths since the 6.5-y follow-up (ie, 5 NIVO + IPI; 3 NIVO; 2 IPI), none were treatment-related; 4 were due to melanoma progression; 1 was due to an unknown cause; and 5 were due to other causes, but not associated with a COVID diagnosis. Conclusions: The 7.5-y follow-up continues to demonstrate the durability of responses with NIVO + IPI and an ongoing survival plateau. A substantial difference in median OS and MSS between patients treated with NIVO + IPI or NIVO was observed in descriptive analyses. Clinical trial information: NCT04540705. [Table: see text]
Percutaneous microwave ablation is comparable to cryoablation for the treatment of T1a renal masses: Results from a cross-sectional study
Authors: L. Boeri, G. Lucignani, A.M. Ierardi, A. Piasentin, C. Trombetta, G. Liguori, M. Bertolotto, M. Rizzo, G. Carrafiello, E. Montanari
Journal: European Urology (2022)